A novel human gammaretrovirus, entropic murine leukemia virus-related virus (XMRV), has been identified in association with familial cases of prostate carcinoma and in patients with chronic fatigue syndrome (CFS). However, the etiological link and the mode of transmission of XMRV remain to be determined. If the roles of XMRV in development of prostate cancer or CFS are established, detection and prevention of XMRV would provide novel intervention strategies for early diagnosis and treatment of both diseases. For better understanding of the XMRV transmission, tissue tropism and pathogenicity, the development of an animal model for XMRV infection is essential. Therefore, our overall goal of this proposal is to develop a small animal model for XMRV infection. Although laboratory mice have provided important small animal model systems for the study of many human diseases, studies of XMRV infection in laboratory mice have been hampered by their lack of a functional XMRV receptor. In our preliminary studies, we have demonstrated that Mus pahari can support XMRV replication in vitro and in vivo. Based on these observations, our central hypothesis is that Mus pahari can serve as a small animal model for XMRV infection. Our specific aims are (i) to determine the modes of transmission and (ii) to determine the pathogenesis of XMRV in Mus pahari. Achieving the specific aims will unveil the potential etiological roles of XMRV and establish the wild-derived mice, Mus pahari, as a small animal model for XMRV infection. This small animal model for XMRV infection would allow in vivo evaluation of anti-XMRV strategies, including small molecules and vaccines. PUBLIC HEALTH RELEVANCE: Xenotropic murine leukemia virus-related virus (XMRV) has been identified in prostate cancer and in patients with chronic fatigue syndrome (CFS), although the etiological link and the mode of transmission remain to be determined. For better understanding of the XMRV transmission, tissue tropism and pathogenicity, the development of an animal model for XMRV infection is essential. Our overall goal of this proposal is to determine the modes of transmission and the pathogenesis of XMRV using wild-derived mice, Mus pahari. Our results will unveil the potential etiological roles of XMRV and establish the wild-derived mice, Mus pahari, as a small animal model for XMRV infection.